Pharmacological agents possessing the ability to block cellular transmembrane influx of calcium are capable of suppressing that portion of myocardial or vascular smooth muscle contractility which is dependent upon extracellular calcium. Church et al., Can. J. Physiol. Pharmacol., 58, 254 (1980); Fleckenstein, Calcium and the Heart, P. Harris and L. Opie, eds., Academic Press (1971); Nayler et al., Bas. Res. Cardiol, 76, 1 (1981); Calcium Blockers, S. Flaim and R. Zelis, eds., Urban and Schwartzenberg, (1982).
These pharmacological agents, termed calcium entry blockers, have been proven to be useful in the treatment of hypertension, cardiac arrhythmias, angina pectoris, and coronary artery vasospasm (a possible cause of sudden cardiac death syndrome). Circ. Res., 52, Suppl. I, (1983); Hypertension 5, Suppl. II, (1983). However, a major limitation and deleterious side-effect for use of some of these agents in certain vascular pathologies is the negative inotropism associated with blockade of cardiac sarcolemmal Ca.sup.+2 channels.
In theory, calcium entry blockers are thought to act by blocking calcium influx through discrete calcium channels (slow channels) in cell membranes. Various tissues exhibit relative differences in sensitivity toward the calcium blocking effect achieved by certain calcium antagonists, theoretically as a result of tissue specific differences in the calcium channels. Acta Pharmacol. Toxicol., 43, 5 (1978); loc. cit. 291 (1978); Microvascular Res., 5, 73 (1973); Am. Rev. Pharmacol. Toxicol., 17, 149 (1977).
A mechanistic difference in Ca.sup.+2 regulation of contractile activity in vascular smooth muscle and cardiac muscle is believed to exist. In cardiac muscle, Ca.sup.+2 regulation is primarily thin filament-linked and involves the troponin-tropomyosin system. Stull et al., Handbook of Physiology, The Cardiovascular System, vol. 1, R. Berne, N. Sperelakis and S. Geiger, eds., American Physiological Society (1979); Solaro, Calcium Blockers, ibid., supra. In vascular smooth muscle, regulation is primarily dependent upon Ca.sup.+2 -calmodulin mediated myosin light chain phosphorylation. Hartshorne et al., Handbook of Physiology, The Cardiovascular System, vol. 2., Bohr, Somlyo and Sparks, eds., American Physiological Society (1982); Silver et al., Calcium Blockers, ibid., supra.
Calcium antagonists which antagonize the effects of Ca.sup.+2 by inhibiting Ca.sup.+2 -calmodulin mediated myosin light chain phosphorylation would be more specific for vascular smooth muscle than cardiac muscle and would be less liable to produce negative inotropic cardiac contraction.
U.S. Pat. Nos. 4,321,384, granted Mar. 31, 1982, and 4,365,063, granted Dec. 21, 1982, disclose hexahydro-2-alkyl-4-aryl-5-oxo-1,7-naphthyridine-3-carboxylic acid esters in which the alcohol derived portion of the ester is an alkyl, alkoxyalkyl, trifluoromethylalkyl or aminoalkyl moiety.